Optically active 1,4-benzodioxine-2-carboxylic acid derivatives and process for producing the same

ABSTRACT

Disclosed are optically active alcohols having formula (1) and (2)                                      
     wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino. The active alcohols can be prepared by acylating a racemate of formula (3)                    
     in the presence of a hydrolase, followed by alcoholysis or hydrolysis. R in formula (3) is the same as that defined for formula (1) and (2).

This is a 371 of PCT/JP99/03963 filed Jul. 23, 1999.

FIELD OF THE INVENTION

The present invention relates to optically active1,4-benzodioxin-2-carboxylic acid derivatives which are intermediatesuseful for the synthesis of (RRR)-optical isomers of1,4-benzodioxin-2-carboxylic acid derivatives which are useful as aprophylactic and therapeutic agent for diabetes, hyperglycemia and thelike, and processes for the preparation thereof. The invention alsorelates to processes for effectively preparing (RRR)-optical isomers of1,4-benzodioxin-2-carboxylic acid derivatives using these intermediates.

BACKGROUND ART

WO 96/35685 discloses an (RRR)-optical isomer of1,4-benzodioxin-2-carboxylic acid derivatives represented by thefollowing general formula (7′) which is useful as a prophylactic andtherapeutic agent for diabetes, hyperglycemia and the like, and aprocess for the preparation thereof.

wherein R₁ is hydroxy or (C₁-C₄)alkoxy, and R₂ and R₃ may be the same ordifferent, and each is hydrogen, halogen, (C₁-C₆)alkyl, trifluoromethyl,(C₁-C₆)alkoxy, aryl, aryloxy or aryl(C₁-C₆)alkyloxy, the aryl, aryloxyor aryl(C₁-C₆)alkyloxy being optionally substituted by one or twohalogens, or R₂ and R₃ may together form —OCH₂O—.

According to a method disclosed in WO 96/35685, a compound of the aboveformula (7′) is prepared as shown in the following Scheme I. A compoundof formula (6) is reductively condensed with a compound of formula (8)to form a mixture of diastereoisomers of formula (9), which is thenconverted into an N-tert-butoxy carbonyl derivative of formula (10), andthe derivative is separated into diastereoisomers of formulae (11) and(12) by column chromatography, and then a compound of formula (11) ishydrolyzed to prepare an (RRR)-optical isomer of1,4-benzodioxin-2-carboxylic acid derivatives represented by the formula(7′).

The above-mentioned process has not been accepted as an efficientmethod, because it forms a compound of formula (12) which is notrequired for the production of a desired compound [formula (7′)], whichresulted in reducing a total yield of the desired compound.

Therefore, it has been demanded to efficiently produce an (RRR)-opticalisomer of 1,4-benzodioxin-2-carboxylic acid derivatives represented bythe formula (7′), which is useful as a prophylactic and therapeuticagent for diabetes, hyperglycemia and the like.

DISCLOSURE OF THE INVENTION

In view of the above-mentioned problems, the present inventors havezealously studied a process for producing efficiently a compound offormula (7′). As a result, the inventors have succeeded in producing thedesired compound in high yield with the reduced formation of unnecessaryoptical isomers and not accompanied by complicated steps. The presentinvention is based on findings that optically active alcohols of thefollowing formulae (1) and (2) are useful as starting materials, whichcan be obtained by acylating racemates of the following formula (3) inthe presence of a hydrolase, followed by separation, and also that thedesired 1,4-benzodioxin-2-carboxylic acid derivative represented by theabove formula (7′) can be produced very efficiently and more selectivelyvia an intermediate of the following formula (7) which can be obtainedby condensing an optically active halogenated product or sulfonylatedproduct (a compound of the following formula (5)) obtained byhalogenating or sulfonylating these starting materials with an(R)-2-amino-1-phenylethanol derivative (a compound of the followingformula (6)).

According to the present invention, a mixture of a compound of formula(2)

wherein R is as defined below and a compound of formula (4)

wherein R is as defined below and X is (C₁-C₄)acyl can be obtained byreacting a racemate of formula (3)

wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino with anacylating agent in the presence of a hydrolase. Separating the resultantmixture can provide each compound with high optical purity and in highyield. Further, the compound of formula (4) obtained above can be easilyconverted by hydrolysis or alcoholysis into a compound of formula (1)

wherein R is as defined above.

Further, a compound of formula (7) (which is an intermediate of formula(7′)),

wherein R is as defined above, and R₂ and R₃ may be the same ordifferent and each is hydrogen, halogen, (C₁-C₆)alkyl, trifluoromethyl,(C₁-C₆)alkoxy, aryl, aryloxy or aryl(C₁C₆)alkyloxy, the aryl, aryloxy oraryl(C₁-C₆)alkyloxy being optionally substituted by one or two halogenatoms, or R₂ and R₃ together may form —OCH₂O—, can be prepared from thecompound of formula (1) or (2) easily and in high yield.

The present invention thus provides the compound of formula (1)

wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino.

The invention also provides the compound of formula (2)

wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino.

Further, the present invention provides a process for preparing thecompound of formula (1)

wherein R is as defined above and the compound of formula (2)

wherein R is as defined above, which comprises the steps of:

reacting the racemate of formula (3)

wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino with anacylating agent in the presence of a hydrolase to give the compound offormula (4)

wherein R is as defined above and X is (C₁-C₄)acyl and the compound offormula (2)

wherein R is as defined above, followed by separation, and subjectingthe compound of formula (4) to alcoholysis or hydrolysis.

Further, the invention provides a process for preparing the compound offormula (7)

wherein R, R₂ and R₃ are as defined below, which comprises the steps of:

reacting the compound of formula (1)

wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino or thecompound of formula (2)

wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino with ahalogenating agent or a sulfonylating agent, and condensing theresulting compound of formula (5)

wherein R is as defined above and Y is halogen, (C₁-C₄)alkylsulfonyloxyor arylsulfonyloxy with the compound of formula (6)

wherein R₂ and R₃ may be the same or different, and each is hydrogen,halogen, (C₁-C₆)alkyl, trifluoromethyl, (C₁-C₆)alkoxy, aryl, aryloxy oraryl(C₁-C₆)alkyloxy, the aryl, aryloxy or aryl(C₁-C₆)alkyloxy beingoptionally substituted by one or two halogen atoms, or R₂ and R₃together may form —OCH₂O—.

The compounds of formulae (1) and (2) are very useful as startingmaterials for the compound of formula (7′) which is useful as medicinesand the compound of formula (7) which is an intermediate for thecompound of formula (7′).

Specific examples of the compounds of formulae (1) and (2) include

6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1(S)-phenylethyl))-2-(R)-carboxamide,

6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1(R)-phenylethyl))-2-(R)-carboxamide,

6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1(R)-phenylethyl))-2-(R)-carboxamide,and

6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1(S)-phenylethyl))-2-(R)-carboxamide.

As shown in the following Scheme II, the racemate of formula (3) isreacted with an acylating agent in the presence of a hydrolase toproduce a mixture of the compound of formula (2) and the compound offormula (4).

(R is as defined above.)

Such a mixture can be separated into each compound by any of knownseparation methods based on differences in physical and chemicalproperties of each compound. These separation methods include fractionalcrystallization, fractional distillation, chromatography, fractionalextraction and the like.

In formula (4), X represents a (C₁-C₄)acyl group, examples of which caninclude acetyl, propionyl, n-butyryl and isobutyryl.

Hydrolases which can be used in the present invention include lipase oresterase, specific examples of which include Candida cylindrarea (tradename “Ald. Type III Lipase”, manufactured by Aldrich), Pseudomonascepacia (trade name “Lipase PS”, manufactured by Amano pharmaceuticalCo., Ltd.), Pseudomonas aeruginosa (trade name “DLIP-300”, manufacturedby Toyobo), Pseudomonas fluorescence (trade name “Lipase AK”,manufactured by Amano pharmaceutical Co., Ltd.), Aspergillus niger(trade name “Lipase A-6”, manufactured by Amano pharmaceutical Co.,Ltd.), Rhizopus oryzae (trade name “Lipase F-AP-15”, manufactured byAmano pharmaceutical Co., Ltd.), Candida cylindracea (trade name “LipaseAY”, manufactured by Amano pharmaceutical Co., Ltd.), Candida rugosa(trade name “Sigma type VII Lipase”, manufactured by Sigma), Mucorjavanicus (trade name “Lipase M”, manufactured by Amano pharmaceuticalCo., Ltd.), Porcine Pancreas Lipase (trade name “Sigma type II Lipase”,manufactured by Sigma), Porcine Liver Esterase (manufactured by Sigma).Pseudomonas fluorescence (trade name “Lipase AK”, manufactured by Amanopharmaceutical Co., LTD.) or Pseudomonas cepacia (trade name “LipasePS”, manufactured by Amano pharmaceutical Co., Ltd.) are particularlypreferable.

An acylating agent used in the present method includes lower fatty acidanhydrides such as acetic anhydride, propionic anhydride and the like,and lower carboxylic esters such as methyl acetate, vinyl acetate,isopropenyl acetate, isopropenyl propionate, isopropenyl butyrate andthe like. Preferred acylating agents are those which do not causeby-products produced by elimination of an acyl group to react reversiblywhen used in acylation, for example, vinyl acetate, isopropenyl acetateand the like, which are converted into acetaldehyde, acetone and thelike. The acylating agent is used in proportion of 1-50 equivalentweights, preferably 3-20 equivalent weights.

Acylation can be carried out without any solvents, i.e., by using anacylating agent per se as a solvent, but in view of easiness in reactionprocesses, it is preferably carried out in the presence of a solvent.The solvents employed are not specifically limited unless giving anyinfluence on the reaction, which can include hydrocarbons such aspentane, hexane, benzene, toluene, xylene and the like; halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachlorideand the like; ethers such as diethyl ether, diisopropyl ether, t-butylmethyl ether, tetrahydrofuran, dioxane and the like; and ketones such asacetone, methyl ethyl ketone and the like, which are used alone or incombination.

The reaction time depends on kinds and amounts of hydrolases used andreaction temperature, but it ranges from one hour to 10 days. Thereaction temperature ranges from room temperature to 40° C., at whichtemperature the deactivation of hydrolases does not occur, and thereaction is preferably performed at the optimum temperature of thehydrolase used.

Separating operation following the acylation is carried out bychromatography, fractional crystallization, fractional extraction or bya combination thereof.

Column carriers employed in chromatography can include, e.g., silicagel, and a mobile phase employed is not specifically limited, unlessgiving any influence on the separation, which can include hydrocarbonssuch as benzene, toluene, xylene, hexane, heptane and the like;halogenated hydrocarbons such as chloroform, methylene chloride, carbontetrachloride and the like; ethers such as diethyl ether, diisopropylether, tetrahydrofuran and the like; alcohols such as methanol, ethanol,isopropanol and the like; acetic acid esters such as ethyl acetate,methyl acetate and the like; ketones such as acetone, methyl ethylketone and the like, or a mixed solvent of these, preferably mixedsolvents of acetic acid esters or ketons with hydrocarbons, inparticular, mixed solvents of ethyl acetate with hexane or acetone withtoluene.

Solvents employed in fractional crystallization are not specificallylimited, unless giving any influence on the recrystallization, which caninclude hydrocarbons such as benzene, toluene, xylene, hexane, heptaneand the like; halogenated hydrocarbons such as chloroform, methylenechloride, carbon tetrachloride and the like; ethers such as diethylether, diisopropyl ether, tetrahydrofuran and the like; alcohols such asmethanol, ethanol, isopropanol and the like; acetic acid esters such asethyl acetate, methyl acetate and the like; ketones such as acetone,methyl ethyl ketone and the like, or a mixed solvent of these,preferably hydrocarbons, a mixed solvent of acetic acid esters andhydrocarbons or a mixed solvent of ethers and hydrocarbons, morepreferably xylene, toluene or a mixed solvent of diisopropyl ether andxylene (mixing ratio 1:99-99:1, v/v). Recrystallization temperaturevaries depending on the conditions of solvents and the like, and usuallyranges from 0° C. to reflux temperature of the solvent used, preferablyfrom 0° C. to room temperature.

Solvents employed in fractional extraction are not specifically limited,unless giving any influence on the separation, which can includehydrocarbons such as benzene, toluene, xylene, hexane, heptane and thelike; halogenated hydrocarbons such as chloroform, methylene chloride,carbon tetrachloride and the like; ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran and the like; alcohols such asmethanol, ethanol, isopropanol and the like; acetic acid esters such asethyl acetate, methyl acetate and the like; ketones such as acetone,methyl ethyl ketone and the like; amides such as dimethylformamide andthe like; sulfoxides such as dimethylsulfoxide and the like; water or amixed solvent of these, preferably a mixed solvent of hydrocarbons,alcohols and water.

The compound of formula (2) thus prepared is used as it is as a startingmaterial of the compound of formula (7), while the compound of formula(4) is converted by hydrolysis or alcoholysis into the compound offormula (1) which is another important starting material.

Acids used for hydrolysis of the compound of formula (4) can includeinorganic acids such as hydrochloric acid, sulfuric acid and the like;organic acids such as acetic acid, methanesulfonic acid, toluenesulfonicacid and the like. Bases used for hydrolysis or alcoholysis can includecarbonates such as sodium carbonate, potassium carbonate, sodiumhydrogencarbonate, potassium hydrogencarbonate and the like; alkalimetal hydroxides such as sodium hydroxide, potassium hydroxide and thelike; organic bases such as trimethylamine, triethylamine,diisopropylamine, diisopropylethylamine, pyridine, quinoline and thelike. The acids or bases can be used in an amount ranging from acatalytic amount to an excess amount, and 0.1-10 equivalent weights ofcarbonates or alkali metal hydroxides may preferably be used.

The hydrolysis is preferably carried out in the presence of solvents inview of easiness in reaction processes. Examples of solvents can includealcohols such as methanol, ethanol, isopropanol and the like; ketonessuch as acetone, methyl ethyl ketone and the like; ethers such asdiethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like;and water. Mixed solvents of alcohols and water are preferred. Thereaction temperature ranges from 0° C. to reflux temperature of solventsemployed, preferably from 0° C. to room temperature. The reaction timeranges from one minute to 72 hours.

As shown in Scheme III, the compounds of formulae (1) and (2) thusprepared can be respectively converted into the compound of formula (5)by halogenation or sulfonylation, followed by condensation with thecompound of formula (6), thus leading to the compound of formula (7).

Examples of halogen represented by Y in the compound of formula (5) caninclude fluorine, chlorine, bromine and iodine. Examples of(C₁-C₄)alkylsulfonyloxy can include methanesulfonyloxy,ethanesulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy andn-butylsulfonyloxy. Examples of arylsulfonyloxy can includebenzenesulfonyloxy and p-toluenesulfonyloxy.

The compound of formula (1) and the compound of formula (2) arerespectively halogenated or sulfonylated, with inversion ofconfiguration for said compound (1) and with retention of configurationfor said compound (2), thereby converting into the compound of formula(5).

The halogenating agent used in halogenation with inversion ofconfiguration can include, for example, acetonitrile and hydrochloricacid (J. Am. Chem. Soc., Vol. 77, 2341, (1955)), dimethylbromosulfoniumbromide (J. C. S. Chem. Commun., 212-213, (1973)), tetramethylα-haloenamine (Tetrahedron Lett., Vol. 30, 3077-3080, (1989)),phosphorus tribromide and phosphorus pentachloride (Synthesis, 1969,112), triphenylphosphine and carbon tetrahalide such as carbontetrachloride and carbon tetrabromide or triphenylphosphine dihalide(Tetrahedron Lett., 2509, (1964), Canad. J. Chem., Vol. 46, 86, (1968))and the like.

The halogenation using triphenylphosphine and carbon tetrahalide, ortriphenylphosphine and bromine or iodine is preferable.Triphenylphosphine is used in the amount of 1-10 equivalent weights andcarbon tetrahalide or bromine or iodine is used in the amount of 1-10equivalent weights. The reaction solvents can include halogenatedhydrocarbons such as methylene chloride, chloroform, dichloroethane,trichloroethane and the like; ethers such as dimethyl ether, diethylether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxaneand the like; hydrocarbons such as pentane, hexane, heptane, benzene,toluene, xylene and the like. Halogenated hydrocarbons such as methylenechloride are preferable. The reaction temperature ranges from 0° C. toreflux temperature of solvents used, preferably from 0° C. to roomtemperature. The reaction time ranges from one minute to 10 hours.

The compound of formula (2) can be converted into the compound offormula (5) with retention of configuration by halogenation with ahalogenating agent such as thionyl chloride, thionyl bromide and thelike or by sulfonylation with a sulfonylating agent such as(C₁-C₄)alkylsulfonyl halides, arylsulfonyl halides and the like.

For the halogenation of the compound of formula (2), halogenating agentssuch as thionyl chloride, thionyl bromide and the like are used in theamount ranging from one equivalent weight to large excess amount. Thereaction can be carried out in the presence or absence of solvents, forexample, hydrocarbons such as pentane, hexane, heptane, benzene,toluene, xylene and the like; halogenated hydrocarbons such as methylenechloride, chloroform, carbon tetrachloride, dichloroethane,trichloroethane and the like. Organic bases such as pyridine, quinoline,triethylamine and the like, unless giving any influence on theconfiguration of a reaction product, may also be used concurrently. Thereaction temperature ranges from −20° C. to reflux temperature of thesolvents used. The reaction time depends on the reagents and solventsused, and usually ranges from one minute to 10 hours.

For the conversion of the compound of formula (2) into the compound offormula (5) in which Y is (C₁-C₄)alkylsulfonyloxy or arylsulfonyloxy,(C₁-C₄)alkylsulfonyl halides such as methanesulfonyl chloride,ethanesulfonyl chloride and the like and arylsulfonyl halides such asbenzenesulfonyl chloride, p-toluenesulfonyl chloride and the like can beused. The solvents used are not specifically limited unless giving anyinfluence on reaction, which can include ethers such as dimethyl ether,diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran,dioxane and the like; polar solvents such as dimethylformamide,dimethylacetamide, dimethylsulfoxide and the like; hydrocarbons such aspentane, hexane, heptane, benzene, toluene, xylene and the like;halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, dichloroethane, trichloroethane and the like. Organicbases such as triethylamine, pyridine, dimethylaminopyridine, quinolineand the like may also be used concurrently. The reaction can be carriedout at the temperature ranging from 0° C. to reflux temperature of thesolvent used, preferably from 0° C. to room temperature.

As described above, either of the compound of formula (1) or thecompound of formula (2), whose configuration is different from eachother, can be converted by halogenation or sulfonylation into the samecompound, i.e., the compound of formula (5). Converting each of thecompounds of formulae (1) and (2) into the compound of formula (5) makesboth the compounds available as a material for preparing the compound offormula (7) and also it advantageously makes subsequent production stepssimplified, thereby obtaining the desired compound efficiently in highyield.

Alternatively, the optically active alcohol of formula (1) is allowed tosterically invert to the optically active alcohol of formula (2), or theoptically active alcohol of formula (2) can be converted into theoptically active alcohol of formula (1).

In general, the methods for the inversion of configuration of theoptically active alcohol can include a method wherein an opticallyactive alcohol is converted into its sulfonic acid ester which is thenreacted with dimethylformamide (J. Am. Chem. Soc., Vol. 80, 2906,(1958)), a method wherein an optically active alcohol is converted intoits sulfonic acid ester which is then reacted with acetic acid (J. Am.Chem. Soc., Vol. 87, 3682, (1965), J. Am. Chem. Soc., Vol. 87, 3686,(1965)), a method wherein an optically active alcohol is converted intoits sulfonic acid ester which is then reacted with tetraalkylammoniumacetate (J. Chem. Soc. (C), 1969, 1605-1606), and a method wherein anoptically active alcohol is led to its alkoxybenzothiazorinium which isthen reacted with trichloroacetic acid (Chem. Lett., 1976, 893-896) andso on. A sterically inverted optically active alcohol can also beobtained by reaction with silver acetate (J. Am. Chem. Soc., Vol. 64,2780 (1942)) following the halogenation with inversion of configurationas discussed above.

For instance, the above method of converting an optically active alcoholinto its sulfonic acid ester followed by reacting with dimethylformamideis accomplished by using one equivalent weight to a large excess ofdimethylformamide after the conversion of the optically active alcoholinto the sulfonic acid ester thereof. The solvents used are notspecifically limited unless giving any influence on the reaction, whichcan include hydrocarbons such as benzene, toluene, xylene, hexane,heptane and the like; halogenated hydrocarbons such as chloroform,methylene chloride, carbon tetrachloride and the like; ethers such asdiethyl ether, diisopropyl ether, tetrahydrofuran and the like; alcoholssuch as methanol, ethanol, isopropanol and the like; acetic acid esterssuch as ethyl acetate, methyl acetate and the like; ketones such asacetone, methyl ethyl ketone and the like; sulfoxides such asdimethylsulfoxide and the like; and water or a mixture of these.Dimethylformamide per se can be used. The reaction is carried out at anytemperature ranging from 0° C. to reflux temperature of the solventsused. The reaction time is from 3 hours to 6 days, depending on solventsand reaction temperature and so on. Preferably, the reaction is carriedout at a temperature ranging from 50° C. to reflux temperature of thesolvent for 3 to 72 hours, using ketones such as methyl ethyl ketone andthe like, sulfoxides such as dimethylsulfoxide and the like, ordimethylformamide per se.

After an intensive conversion into the compound of either formula (1) or(2) in the above manner, it is also possible to subject each compound tothe above halogenation or sulfonylation, thereby leading to the compoundof formula (5).

The compound of formula (5) obtained as described above is condensedwith the compound of formula (6) into the compound of formula (7).

This condensation reaction is carried out by using 1 to 20 equivalentweights of the compound of formula (6) in the absence or presence ofsolvents. The solvents which may be used include ethers such as dimethylether, diethyl ether, diisopropyl ether, t-butyl methyl ether,tetrahydrofuran, dioxane and the like; aprotic polar solvents such asdimethylformamide, dimethylacetamide, dimethylsulfoxide and the like;hydrocarbons such as pentane, hexane, heptane, benzene, toluene, xylene,and the like; and halogenated hydrocarbons such as methylene chloride,chloroform, carbon tetrachloride dichloroethane, trichloroethane and thelike. The reaction can be carried out in the presence of bases such asorganic bases, for example, triethylamine, pyridine, quinoline and thelike, or inorganic bases, for example, sodium hydrogencarbonate,potassium hydrogencarbonate, sodium carbonate, potassium carbonate,sodium hydroxide, potassium hydroxide and the like. The reactiontemperature ranges from room temperature to reflux temperature of thesolvent used. The reaction time ranges from one hour to 72 hours.

The compound of formula (7) thus obtained can be converted by hydrolysisinto a compound of formula (7′) wherein R₁ is a hydroxy group, which isa useful end product as medicines as described above. The hydrolysis canbe carried out using inorganic bases such as sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate and the like, orinorganic acids such as sulfuric acid, hydrochloric acid and the like.The solvents used can include water; alcohols such as methanol, ethanol,isopropanol, butanol, t-butyl alcohol and the like; organic acids suchas formic acid, acetic acid, propionic acid and the like; and a mixturethereof. The reaction temperature ranges from room temperature to refluxtemperature of the solvent used. The reaction time ranges from 10minutes to 72 hours.

Further, the compound of formula (7′) wherein R₁ is a hydroxy group maybe esterified and isolated as a compound of formula (7′) wherein R₁ is a(C₁-C₄)alkoxy group, without isolation as the carboxylic acid afterhydrolysis of the compound of formula (7). More specifically, an estercompound of formula (7′) can easily be prepared by distilling off thesolvent under reduced pressure after completion of hydrolysis of thecompound of formula (7), adding to the residue (C₁-C₄)alcohols such asmethanol, ethanol, propanol and the like, and then esterifying underacidic conditions. The acids used can include usual inorganic acids suchas hydrochloric acid, sulfuric acid and the like. The reactiontemperature ranges from 0° C. to reflux temperature of the alcohol used.The reaction time ranges from one minute to 10 hours.

Further, the compound of formula (7′) wherein R₁ is a (C₁-C₄)alkoxygroup can be again and easily converted by hydrolysis into the compoundof formula (7′) wherein R₁ is a hydroxy group.

The hydrolysis can be carried out by using inorganic bases such assodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and thelike or inorganic acids such as hydrochloric acid, sulfuric acid and thelike, in water or in a mixed solution of water and solvents, forexample, alcohols such as methanol, ethanol, propanol, butanol and thelike, acetonitrile, propionitrile, tetrahydrofuran, dioxane and thelike. The reaction is carried out at a temperature ranging from roomtemperature to reflux temperature and completed in 10 minutes to 10hours.

Racemates of formula (3) used as a starting material in the presentinvention can be synthesized as shown in the following scheme IV,starting from a compound of formula (13), via a compound of formula (15)condensed with nitroethane and reducing a compound of formula (8′) inaccordance with the process described in WO 96/35685.

(R represents (R)-1-phenylethylamino or (S)-1-phenylethylamino.)

The present invention has been mentioned only about the preparation of1,4-benzodioxin-2-carboxylic acid derivatives of formulae (1) and (2)starting from the compound of formula (13) wherein R is an opticallyactive phenylethylamino group. These 1,4-benzodioxin-2-carboxylic acidderivatives have the advantages that they are more chemically stable andare more difficult to be isomerized, as compared with conventional1,4-benzodioxin-2-carboxylic acid derivatives starting from the compoundof formula (13) wherein R is a (C₁-C₄)alkoxy group disclosed in WO96/35685.

The reaction converting from a compound of formula (13) to a compound offormula (14) is carried out in the presence of primary amines and in theabsence or presence of solvents. The reaction is carried out whiledehydrating with Dean-Stark or using dehydrating agents such asanhydrous sodium carbonate, anhydrous potassium carbonate, anhydroussodium sulfate, anhydrous magnesium sulfate, molecular sieves and thelike. The primary amines used can include cyclohexylamine, methylamine,ethylamine and n-butylamine.

The solvents are not specifically limited unless giving any influence onthe reaction, which can include ethers such as dimethyl ether, diethylether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxaneand the like; alcohols such as methanol, ethanol, isopropanol, butanol,t-butyl alcohol and the like; aprotic polar solvents such asdimethylformamide, dimethylacetamide, dimethylsulfoxide and the like;hydrocarbons such as pentane, hexane, heptane, benzene, toluene, xyleneand the like; halogenated hydrocarbons such as methylene chloride,chloroform, carbon tetrachloride, dichloroethane, trichloroethane andthe like. The reaction can be carried out at a temperature ranging from0° C. to reflux temperature of the solvent used. The reaction timeusually ranges from 10 minutes to 10 hours, depending on the solventsused and a reaction temperature and so on. Preferably, the reaction canbe performed for 1-5 hours, using hydrocarbons as a solvent under thereflux. More preferably, the reaction can be conducted for 1-3 hours,dehydrating in benzene under reflux.

The reaction converting from a compound of formula (14) to a compound offormula (15) is performed, using an acid in the absence or presence ofsolvents. The acids used can include inorganic acids such ashydrochloric acid, sulfuric acid and the like; organic acids such asacetic acid, propionic acid and the like; sulfonic acids such asmethanesulfonic acid, toluenesulfonic acid, camphorsulfonic acid and thelike. The solvents are not specifically limited unless giving anyinfluence on the reaction, which can include ethers such as dimethylether, diethyl ether, diisopropyl ether, t-butyl methyl ether,tetrahydrofuran, dioxane and the like; alcohols such as methanol,ethanol, isopropanol, butanol, t-butyl alcohol and the like; aproticpolar solvents such as dimethylformamide, dimethylacetamide,dimethylsulfoxide and the like; hydrocarbons such as pentane, hexane,heptane, benzene, toluene, xylene and the like; halogenated hydrocarbonssuch as methylene chloride, chloroform, carbon tetrachloride,dichloroethane, trichloroethane and the like; organic acids such asacetic acid, propionic acid and the like. They can be used alone or incombination. The reaction can be carried out at a temperature rangingfrom 0° C. to reflux temperature of the solvent used. The reaction timevaries depending on the solvents used and a reaction temperature, butusually ranges from 10 minutes to 10 hours. Preferably, the reaction canbe carried out for 1-5 hours under the reflux, using organic acids suchas acetic acid, propionic acid and the like as a solvent.

The reaction converting from a compound of formula (15) to a compound offormula (8′) is carried out in the presence of a reducing agent. Thereducing agents used can include metallic powders such as iron powder,zinc powder, copper powder and the like. The reaction is conducted inthe presence of solvents. The solvents used are not specifically limitedunless giving any influence on the reaction, which can include etherssuch as tetrahydrofuran, dioxane and the like; alcohols such asmethanol, ethanol, isopropanol, butanol, t-butyl alcohol and the like;aprotic polar solvents such as dimethylformamide, dimethylacetamide,dimethylsulfoxide and the like; organic acids such acetic acid,propionic acid and the like, and a mixed solvent of these. The reactioncan be carried out at a temperature ranging from 0° C. to refluxtemperature of the solvent used. The reaction time varies depending onsolvents employed and a reaction temperature, but usually ranges from 10minutes to 10 hours. Preferably, the reaction is carried out for 15hours under the reflux, using a mixed solvent of water and alcohols suchas methanol, ethanol and the like and organic acids such as acetic acidand the like.

The reaction converting from a compound of formula (8′) to a compound offormula (3) is performed with a reducing agent. The reducing agents usedcan include metal hydrides such as lithium aluminum hydride (LiAlH₄),sodium borohydride (NaBH₄), lithium borohydride (LiBH₄), diborane (B₂H₆)and the like, and sodium borohydride or lithium borohydride ispreferably used. The solvents which can be used depend on a reducingagent employed, which can include ethers such as diethyl ether, THF,dioxane and the like; alcohols such as methanol, ethanol, propanol andthe like; and aromatic hydrocarbons such as benzene, toluene and thelike.

The reaction temperature ranges from −20° C. to reflux temperature ofsolvents, preferably from 0° C. to room temperature. The reaction timedepends on a reducing agent and solvents used, but ranges from oneminute to 10 hours. Preferably, the reaction is carried out using sodiumborohydride as a reducing agent in ethers or alcohols at a temperatureof from 0° C. to room temperature for 30 minutes to 3 hours.

Optically active alcohols of formulae (1) and (2) according to thepresent invention are very useful as intermediates for the synthesis of1,4-benzodioxin-2carboxylic acid derivatives of formula (7′), which areuseful as medicines, in high yield and with high optical purity.

According to the present invention, intermediates for the synthesisrepresented by formulae (1) and (2) can be also obtained in high yieldand with high optical purity.

The present invention is illustrated in detail by the following examplesand reference examples.

Analytical conditions for high performance liquid chromatography (HPLC)to determine optical purity and so on shown in examples are describedbelow.

HPLC-1

Column: DEVELOSIL 60-3, 4.6 mm×500 mm (Nomura Chemical Co., LTD.)

Mobile phase: hexane/ethyl acetate/acetic acid=600/400/5

Flow rate: 1.0 ml/min

Detection: UV 280 nm

HPLC-2

Column: YMC CHIRAL NEA(R), 4.6 mm×300 mm (YMC Co., LTD.)

Mobile phase: 0.5N sodium perchlorate-perchloric acid (pH2.0)/acetonitrile =1/1

Flow rate: 1.0 ml/min

Detection: UV 280 nm

HPLC-3

Column: Nucleosil 50-5, 4.6 mm×250 mm

Mobile phase: ethyl acetate/hexane =1/1 (v/v)

Flow rate: 1.0 ml/min

Detection: UV 280 nm

Retention time: acetate 6.8 min, S alcohol 14.3 min, R alcohol 14.8 min

The purities of optical isomers of formulae (1) and (2) are expressed interms of values which are determined at the position of asymmetriccarbon atoms in “hydroxypropyl” in the compounds. The purities ofoptical isomers of formulae (7) and (7′) are expressed in terms ofvalues which are determined at the position of asymmetric carbon atomsin “aminopropyl”, in the compounds. The compound of formula (6) used isof optical purity 100%, and the starting material used in ReferenceExample 1 is of diastereomeric excess 97-99%.

EXAMPLE 1

a)6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide

To a suspension of6-(2-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)carboxamide (1.1 g) in t-butyl methyl ether (200 ml) were added vinylacetate (27 ml), 2,6-di-t-butyl-p-cresol (6.5 mg) and lipase PS (1.0 g,manufactured by Amano Pharmaceutical Co., Ltd.), and this mixture wasstirred at 37° C. for 132 hours and at room temperature for 62 hours(The reaction was followed by HPLC 3, and stopped at the time of 50%acylation attained). After the reaction solution was filtered throughCelite, the solvent was distilled off under reduced pressure. Theresidue was chromatographed over silica gel to give6-(2-(R)-acetoxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(574 mg) as colorless crystals from the fraction of ethyl acetate/hexane(1/3) and6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(510 mg, yield=46.4%) as colorless crystals from the fraction of ethylacetate/hexane (1/1). The HPLC-1 analysis of the latter showed 95.1%purity for the optical isomer (S-alcohol isomer/R-alcoholisomer=95.1/4.9).

6-(2-(R)-acetoxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide

¹H-NMR (CDCl₃) δ: 1.20 (d, J=5.9 Hz, 3H), 1.55 (d, J=6.8 Hz, 3H), 2.00(s, 3H), 2.65 (dd, J=6.3, 13.7 Hz, 1H), 2.82 (dd, J=6.8, 14.2 Hz, 1H),4.12 (dd, J=7.3, 11.2 Hz, 1H), 4.51 (dd, J=2.4, 11.2 Hz, 1H), 4.69 (dd,J=2.4, 7.3 Hz, 1H), 5.05 (sixt., J=6.3 Hz, 1H), 5.18 (quint., J=7.3 Hz,1H), 6.71 (dd, J=2.0, 8.3 Hz, 1H), 6.74 (d, J=2.0 Hz, 1H), 6.78 (brd,J=8.3 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 7.15-7.35 (m, 5H).

6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide

¹H-NMR (CDCl₃) δ: 1.22 (d, J=5.9 Hz, 3H), 1.55 (d, J=6.8 Hz, 3H), 1.62(brs, 1H, D₂O exchangeable), 2.59 (dd, J=7.8, 13.7 Hz, 1H), 2.69 (dd,J=4.9, 13.7 Hz, 1H), 3.96 (sixt., J=6.3 Hz, 1H), 4.14 (dd, J=7.3, 11.7Hz, 1H), 4.51 (dd, J=2.9, 11.7 Hz, 1H), 4.69 (dd, J=2.4, 7.3 Hz, 1H),5.18 (quint., J=7.3 Hz, 1H), 6.77 (s, 1H), 6.79 (brs, 1H), 6.90 (d,J=8.3 Hz, 1H), 7.15-7.27 (m, 5H).

b)6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N(1-(S)-phenylethyl))-2-(R)-carboxamide

To a solution of6-(2-(R)-acetoxypropyl)--2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(574 mg) obtained in a) above in methanol (5 ml) was added potassiumcarbonate (6.2 mg), and the solution was stirred at room temperature for12 hours. Potassium carbonate (14.5 mg) was further added, and themixture was stirred for 14 hours. The solvent was distilled off underreduced pressure. The residue was dissolved in ethyl acetate, and washedwith water. The resulting solution was dried over magnesium sulfate togive6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(550 mg, yield=50%). The HPLC-1 analysis of the optical isomer showed83.0% purity (S-alcohol isomer/R-alcohol isomer=17.0/83.0).

¹H-NMR (CDCl₃) δ: 1.22 (d, J=5.9 Hz, 3H), 1.55 (d, J=6.8 Hz, 3H), 1.62(brs, 1H, D₂O exchangeable), 2.59 (dd, J=7.8, 13.7 Hz, 1H), 2.69 (dd,J=4.9, 13.7 Hz, 1H), 3.96 (sixt., J=6.3 Hz, 1H), 4.14 (dd, J=7.3, 11.7Hz, 1H), 4.51 (dd, J=2.9, 11.7 Hz, 1H), 4.69 (dd, J=2.4, 7.3 Hz, 1H),5.18 (quint., J=7.3 Hz, 1H), 6.77 (s, 1H), 6.79 (brs, 1H), 6.90 (d,J=8.3 Hz, 1H), 7.15-7.27 (m, 5H).

EXAMPLE 2

a) To a solution of6-(2-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(1.0 g) in tetrahydrofuran (20 ml) were added vinyl acetate (13.5 ml)and 2,6-di-t-butyl-p-cresol (6.4 mg). This solution was stirred at 37°C. on a water bath, lipase AK (500 mg, manufactured by AmanoPharmaceutical Co., Ltd.) was added thereto, and the mixture was stirredat 37° C. on a water bath for 51 hours. The reaction solution wasfiltered through Celite, and then concentrated under reduced pressure.The residue was chromatographed over silica gel to give6-(2-(R)-acetoxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(510 mg, yield=46%) from the fraction of ethyl acetate/hexane (2/3) and6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(440 mg, yield=44%) from the fraction of ethyl acetate/hexane (3/2). TheHPLC-1 analysis of the optical isomer showed 97.9% purity (S-alcoholisomer/R-alcohol isomer=97.9/2.1).

b) To a solution of6-(2-(R)-acetoxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(510 mg) obtained in a) above in methanol (15 ml) was added potassiumcarbonate (40 mg), and the solution was stirred at room temperature for9 hours. The reaction solution was concentrated under reduced pressure,and the residue was chromatographed over silica gel to give6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(430 mg, yield=43%) from the fraction of ethyl acetate/hexane (3/2). TheHPLC-1 analysis of the optical isomer showed 96.9% purity (S-alcoholisomer/R-alcohol isomer=3.1/96.9).

EXAMPLE 3

6-(2-(R)-Hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(yield=21%, the purity of the optical isomer=70.0% by HPLC-1analysis(S-alcohol isomer/R-alcohol isomer=30/70)) was prepared in asimilar manner as in Example 1 a), except for using t-butyl methyl etheras a solvent and DLIP-300 (manufactured by Toyobo) as lipase.6-(2-(S)hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(yield=79%, the purity of the optical isomer=54.2% by HPLC-1 analysis(S-alcohol isomer/R-alcohol isomer=54.2/45.8)) was also obtained in asimilar way as in Example 1 b). Yield was calculated by HPLC-3 analysis.

EXAMPLE 4

6-(2-(S)-Hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(yield=52%, the purity of the optical isomer=96.4% by HPLC-1 analysis(S-alcohol isomer/R-alcohol isomer=96.4/3.6)) was obtained in a similarway as in Example 1 a), except for using toluene as a solvent and lipaseAK (manufactured by Amano Pharmaceutical Co., Ltd.) as lipase.6-(2-(R)Hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(yield=48%, the purity of the optical isomer=91.1% by HPLC-1 analysis(S-alcohol isomer/R-alcohol isomer=8.9/91.1)) was also obtained in asimilar way as in Example 1 b). Yield was calculated by HPLC-3 analysis.

EXAMPLE 5

6-(2-(S)-Hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide (yield=50%, thepurity of the optical isomer=94.1% by HPLC-1 analysis (S-alcoholisomer/R-alcohol isomer=94.1/5.9)) was obtained in a similar way as inExample 1 a), except for using methyl ethyl ketone as a solvent andlipase AK (manufactured by Amano Pharmaceutical Co., Ltd.) as lipase.6-(2-(R)-Hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(yield=50%, the purity of the optical isomer=97.6% by HPLC-1 analysis(S-alcohol isomer/R-alcohol isomer=2.4/97.6)) was also obtained in asimilar way as in Example 1 b). Yield was calculated by HPLC-3 analysis.

EXAMPLE 6

6-(2-(S)-Hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(yield=51%, the purity of the optical isomer=98.5% by HPLC-1 analysis(S-alcohol isomer/R-alcohol isomer=98.5/1.5)) was obtained in a similarway as in Example 1 a), except for using acetonitrile as a solvent andlipase AK (manufactured by Amano Pharmaceutical Co., Ltd.) as lipase.6-(2-(R)-Hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(yield=49%, the purity of the optical isomer=95.0% by HPLC-1 analysis(S-alcohol isomer/R-alcohol isomer=5.0/95.0)) was also obtained in asimilar way as in Example 1 b). Yield was calculated by HPLC-3 analysis.

EXAMPLE 7

6-(2-(S)-(p-Toluenesulfonyloxy)propyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide

To a solution of6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(1.6 g) in methylene chloride (15 ml) were added 4-dimethylaminopyridine(860 mg) and p-toluenesulfonyl chloride (1.34 g) at room temperature,and the mixture was stirred for 24 hours. To the reaction solution wasadded chloroform, and this solution was washed in turn with dilutehydrochloric acid, aqueous sodium hydrogencarbonate and saturated brine,and dried over magnesium sulfate. The solvent was distilled off underreduced pressure. The residue was chromatographed over silica gel togive6-(2-(S)-(p-toluenesulfonyloxy)propyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(2.18 g, yield=94%) as a colorless oil from the fraction of ethylacetate/hexane (1/2).

¹H-NMR (CDCl₃) δ: 1.24 (d, J=6.3 Hz, 3H), 1.55 (d, J=6.8 Hz, 3H), 1.60(d, J=11.4 Hz, 1H), 2.41 (s, 3H), 2.68 (dd, J=6.8 , 13.7 Hz, 1H), 2.82(dd, J=6.3, 14.2 Hz, 1H), 4.05-4.15 (m, 1H), 4.51 (dd, J=2.9, 11.7 Hz,1H), 4.65-4.72 (m, 1H), 5.27 (quint., J=7.8 Hz, 1H), 6.40-6.65 (m, 2H),6.75-6.85 (m, 2H), 7.15-7.33 (m, 6H), 7.68 (d, J=8.3 Hz, 2H)

EXAMPLE 8

6-(2-(R)-(p-Toluenesulfonyloxy)propyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide

6-(2-(R)-(p-Toluenesulfonyloxy)propyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)carboxamidewas obtained in 64% yield in a similar way as in Example 7 from6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide.

¹H-NMR (CDCl₃) δ: 1.24 (d, J=6.3 Hz, 3H), 1.55 (d, J=6.8 Hz, 3H), 1.60(d, J=11.4 Hz, 1H), 2.41 (s, 3H), 2.68 (dd, J=6.8, 13.7 Hz, 1H), 2.82(dd, J=6.3, 14.2 Hz, 1H), 4.05-4.15 (m, 1H), 4.51 (dd, J=2.9, 11.7 Hz,1H), 4.65-4.72 (m, 1H), 5.27 (quint., J=7.8 Hz, 1H), 6.40-6.65 (m, 2H),6.75-6.85 (m, 2H), 7.15-7.33 (m, 6H), 7.68 (d, J=8.3 Hz, 2H)

EXAMPLE 9

To a solution of6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(1.0 g) in methylene chloride (12 ml) were added triphenylphosphine(1.15 g) and carbon tetrabromide (1.46 g). The solution was stirred atroom temperature for 3 hours and then washed in turn with a saturatedaqueous solution of sodium hydrogencarbonate and saturated brine, driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue was chromatographed over silica gel to give6-(2(S)-bromopropyl-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(940 mg, yield=79%) from the fraction of ethyl acetate/hexane (1/2).

¹H-NMR (CDCl₃) δ: 1.55 (d, 3H, J=8.4 Hz), 1.67 (d, 3H, J=6.8 Hz), 2.97(dd, 1H, J=7.2 Hz, 14.4 Hz), 3.11 (dd, 1H, J=7.2 Hz, 14.4 Hz), 4.09-4.28(m, 2H), 4.51 (dd, 1H, J=2.8 Hz, 11.6 Hz), 4.70 (dd, 1H, J=2.8 Hz, 7.6Hz), 5.18 (quint. 1H, 7.2 Hz), 6.68-6.80 (m, 3H), 6.85-6.92 (m, 1H),7.15-7.33 (m, 5H)

EXAMPLE 10

To a solution of6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(1.0 g) in carbon tetrachloride (15 ml) was added triphenylphosphine(1.23 g). This solution was stirred under reflux for 6 hours, and ethylacetate was added thereto. The mixture was filtered through Celite, andthen concentrated under reduced pressure. The residue waschromatographed over silica gel to give6-(2-(S)-chloropropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(780 mg, yield=74%) from the fraction of ethyl acetate/hexane (1/2).

¹H-NMR (CDCl₃) δ: 1.48 (d, 3H, J=6.8 Hz), 1.55 (d, 3H, J=6.8 Hz), 2.87(dd, 1H, J=6.8 Hz, 14.4 Hz), 2.97 (dd, 1H, J=6.8 Hz, 14.4 Hz), 4.08-4.21(m, 2H), 4.51 (dd, 1H, J=2.4 Hz, 11.2 Hz), 4.70 (dd, 1H, J=2.4 Hz, 7.2Hz), 5.18 (quint, 1H, J=7.2 Hz), 6.70-6.82 (m, 3H), 6.85-6.93 (m, 1H),7.15-7.32 (m, 5H).

EXAMPLE 11

To a solution of6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(200 mg) in tetrahydrofuran (6 ml) and acetonitrile (2 ml) were added inturn triphenylphosphine (185 mg), imidazole (48 mg) and iodine (179 mg)at room temperature. The mixture was stirred for 5 hours, andtriphenylphosphine (185 mg), imidazole (48 mg) and iodine (90 mg) werefurther added thereto. After stirring for ten minutes, ethyl acetate wasadded to the reaction solution. This solution was washed in turn with asaturated aqueous solution of sodium hydrogencarbonate, a 10% aqueoussolution of sodium thiosulfate and saturated brine, and then dried oversodium sulfate. The solvent was distilled off under reduced pressure.The residue was chromatographed over silica gel to give6-(2-(S)-iodopropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(230mg, yield=87%) from the fraction of ethyl acetate/hexane (1/3-1/2).

¹H-NMR (CDCl₃) δ: 1.55 (d, J=6.8 Hz, 3H), 1.88 (d, J=6.8 Hz, 3H), 2.96(dd, J=7.3, 14.2 Hz, 1H), 3.17 (dd, J=7.3, 14.2 Hz, 1H), 4.15 (dd,J=7.3, 12.2 Hz, 1H), 4.27 (dd, J=7.3, 14.2 Hz, 1H), 4.51 (dd, J=2.9,11.2 Hz, 1H), 4.70 (dd, J=2.9, 7.3 Hz, 1H), 5.18 (quint., J=7.3 Hz, 1H),6.70 (dd, J=2.0, 8.3 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 6.77 (brd, J=8.0Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 7.15-7.32 (m, 5H).

EXAMPLE 12

6-(2-(R)-((2-(R)-(3-Chlorophenyl)-2-hydroxyethyl)amino)-propyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide

To6-(2-(S)-chloropropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(360 mg) was added (R)-2-amino-1-(3-chlorophenyl)-ethanol (686 mg), themixture was stirred at 130° C. for 14 hours, and then ethyl acetate wasadded thereto. The reaction solution was washed in turn with a saturatedaqueous solution of sodium hydrogencarbonate and saturated brine, thendried over sodium sulfate and concentrated under reduced pressure. Theresidue was chromatographed over silica gel to give6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)-propyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(150 mg, yield=30%) from the fraction of methanol/ethyl acetate/aqueousammonia (10/90/1). The HPLC-2 analysis of the optical isomer showed91.5% purity (R/S=91.5/8.5, the purity of the material optical isomerused=97.5%).

¹H-NMR (CDCl₃) δ: 1.08 (d, J=6.3 Hz, 3H), 1.55 (d, J=7.3 Hz, 3H),2.50-2.95 (m, 7H, 2H:D₂O exchangeable), 4.12 (dd, J=7.3, 11.2 Hz, 1H),4.52 (dd, J=2.4, 11.2 Hz, 1H), 4.58 (dd, J=3.4, 8.8 Hz, 1H), 4.69 (dd,J=2.4, 7.3 Hz, 1H), 5.18 (quint., J=7.3 Hz, 1H), 6.68 (dd, J=2.0, 8.3Hz, 1H), 6.72 (d, J=1.5 Hz, 1H), 6.79 (brd, J=8.3 Hz, 1H), 6.89 (d,J=8.3 Hz, 1H), 7.15-7.35 (m, 9H).

EXAMPLE 13

To6-(2-(S)-iodopropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(450 mg) was added (R)-2-amino-1-(3-chlorophenyl)-ethanol (686 mg), themixture was stirred at 100° C. for one hour, and then ethyl acetate wasadded thereto. After this reaction solution was washed in turn with asaturated aqueous solution of sodium hydrogencarbonate and saturatedbrine, dried over sodium sulfate and then concentrated under reducedpressure. The residue was chromatographed over silica gel to give6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(180 mg, yield=36%) from the fraction of methanol/ethyl acetate/aqueousammonia (10/90/1). The HPLC-2 analysis of the optical isomer showed 73%purity (R/S=73/27, the purity of the material optical isomerused=97.5%).

EXAMPLE 14

To6-(2-(S)-bromopropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(280 mg) was added (R)-2-amino-1-(3-chlorophenyl)-ethanol (177 mg), themixture was stirred at 100° C. for one hour, and then chloroform wasadded thereto. This reaction solution was washed in turn with asaturated aqueous solution of sodium hydrogencarbonate and saturatedbrine, dried over sodium sulfate, and then concentrated under reducedpressure. The residue was chromatographed over silica gel to give6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)-propyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(160 mg, yield=32%) from the fraction of methanol/ethyl acetate/aqueousammonia (10/90/1). The HPLC-2 analysis of the optical isomer showed 75%purity (R/S=75/25, the purity of the material optical isomerused=97.5%).

EXAMPLE 15

To6-(2-(S)-(p-toluenesulfonyloxy)propyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(48.3 g) was added (R)-2-amino-1-(3-chlorophenyl)-ethanol (66.9 g)dissolved in a small amount of methylene chloride. The mixture wasconcentrated under reduced pressure. After removing methylene chloride,the solution was stirred at 70-85° C. for 4 hours. Ethyl acetate (1.0 L)was added to the reaction solution, and the solution was twice washedwith a saturated aqueous solution of sodium hydrogencarbonate, driedover sodium sulfate, and concentrated under reduced pressure. Theresidue was chromatographed over silica gel to give6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(34.5 g, yield=71%) from the fraction of methanol/ethyl acetate/aqueousammonia (10/90/1). The HPLC-2 analysis of the optical isomer showed92.2% purity (R/S=92.2/7.8, the purity of the material optical isomerused=97.5%).

EXAMPLE 16

To a solution of6-(2-(S)-iodopropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(450 mg) in toluene (6 ml) were added(R)-2-amino-1-(3-chlorophenyl)-ethanol (343 mg) and sodiumhydrogencarbonate (252 mg), and the mixture was stirred underreflux-heating for 61 hours. To the reaction solution was added water,and the mixture was extracted with ethyl acetate. The organic layer wasdried over sodium sulfate and then concentrated under reduced pressure.The residue was chromatographed over silica gel to give6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(210 mg, yield=42%) from the fraction of methanol/ethyl acetate/aqueousammonia (10/90/1). The HPLC-2 analysis of the optical isomer showed67.5% purity (R/S=67.5/32.5, the purity of the material optical isomerused=97.5%).

EXAMPLE 17

6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamidewas obtained in 34% yield in a similar way as in Example 16, except forusing6-(2-(S)-bromopropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamideas a starting material and potassium carbonate as a base. The HPLC-2analysis of the optical isomer showed 96.5% purity (R/S=96.5/3.5, thepurity of the material optical isomer used=97.5%).

EXAMPLE 18

Ethyl6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-2,3-dihydro-1,4-benzodioxin-2-(R)-carboxylate

To a solution of6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(1.0 g) in acetic acid (12 ml) and water (12 ml) was added concentratedsulfuric acid (1.5 ml), and the mixture was stirred at 100° C. for 42hours. After the solution was concentrated under reduced pressure, theresidue was dissolved in ethanol (20 ml) and the solution was againconcentrated under reduced pressure. This procedure was carried outthree times, the resulting solution was partitioned between ethylacetate and a saturated aqueous solution of sodium hydrogencarbonate,and the ethyl acetate layer was washed with saturated brine, dried oversodium sulfate, and concentrated under reduced pressure. The residue waschromatographed over silica gel to give ethyl6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)-propyl)-2,3-dihydro-1,4-benzodioxin-2-(R)-carboxylate(690 mg, yield=82%) from the fraction of methanol/ethyl acetate/aqueousammonia (10/90/1). The HPLC-2 analysis of the optical isomer showed90.5% purity (R/S=90.5/9.5, the purity of the material optical isomerused=90.5%).

¹H-NMR (CDCl₃) δ: 1.06 (d, J=6.3 Hz, 3H), 1.29 (t, J=7.3 Hz, 3H),2.50-2.65 (m, 3H), 2.84-2.91 (m, 2H), 4.22-4.32 (m, 2H), 4.37 (d, J=3.4Hz, 2H), 4.52 (dd, J=3.4, 8.8 Hz, 1H), 4.80 (t, J=3.9 Hz, 1H), 6.64-6.73(m, 2H), 6.93 (d, J=8.3 Hz, 1H), 7.19-7.30 (m, 3H), 7.35 (s, 1H).

EXAMPLE 19

6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)-propyl)-2,3-dihydro-1,4-benzodioxin-2-(R)-carboxylicacid

To a solution of ethyl6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-2,3-dihydro-1,4-benzodioxin-2-(R)-carboxylate(650 mg) in ethanol (2 ml) were added water (20 ml) and concentratedhydrochloric acid (0.32 ml). This solution was stirred underreflux-heating for 5 hours while removing ethanol with Dean-Starkapparatus. After the solution was concentrated under reduced pressure,acetonitrile/water (1/1) (11 ml) was added to the residue, which wasthen dissolved under heating. The solution was neutralized with a 5%aqueous solution of sodium hydrogencarbonate. Acetonitrile (20 ml) wasadded, and the crystals precipitated were dissolved under heating. Theresulting solution was filtered under heating and then cooled, and theresulting crystals were filtered to give6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)-propyl)-2,3-dihydro-1,4-benzodioxin-2-(R)-carboxylicacid (412 mg). The HPLC-2 analysis of the optical isomer showed 96.5%purity (R/S=96.5/3.5, the purity of the material optical isomerused=90.5%).

White crystals, m.p. 243-244° C. (dec.)

¹H-NMR (DMSO-d₆) δ: 0.81 (d, J=6.3 Hz, 3H), 1.88 (t, J=12.2 Hz, 1H),2.26 (d, J=11.7 Hz, 1H), 2.80 (dt, J=11.2 Hz, 1H), 3.00-3.17 (m, 2H),4.10 (d, J=8.8 Hz, 1H), 4.52 (brd, J=10.2 Hz, 1H), 4.67 (s, 1H), 5.19(brd, J=8.8 Hz, 1H), 6.26 (brd, J=8.3 Hz, 1H), 6.39 (brs, 1H), 6.74 (d,J=8.3 Hz, 1H), 7.30-7.42 (m, 3H), 7.47 (brs, 1H).

¹³C-NMR (DMSO-d₆) δ: 13.8, 37.6, 51.5, 55.0, 66.1, 66.8, 72.8, 116.7,117.4, 121.6, 124.6, 125.7, 127.3, 129.0, 130.2, 133.1, 142.1, 142.9,144.7, 172.9.

EXAMPLE 20

To a solution of6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(21 g) in acetic acid (100 ml) and water (100 ml) was added concentratedsulfuric acid (10 ml). This solution was stirred at external temperatureof 120° C. for 58 hours. After the solution was cooled to roomtemperature, the pH was adjusted to about 3 with an aqueous solution ofsodium acetate. The solution was extracted with chloroform, andconcentrated under reduced pressure. To the residue was addedacetonitrile/water (1/1) (210 ml) and the residue was dissolved underheating. The solution was neutralized with a saturated aqueous solutionof sodium hydrogencarbonate, and about a half amount of the reactionsolution was concentrated under ordinary pressure. The insolublesprecipitated were dissolved under heating with ethanol (300 ml) andwater (100 ml), and then the solution was cooled on an ice bath. Theresulting crystals were filtered off to give6-(2-(R)-((2-(R)-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-2,3-dihydro-1,4-benzodioxin-2-(R)-carboxylicacid (7.04 g). The HPLC-2 analysis of the optical isomer showed 97.4%purity (R/S=97.4/2.6, the purity of the material optical isomerused=84.3%).

EXAMPLE 21

6-(2-(R)-Hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide

To a solution of6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(0.5 g) in tetrahydrofuran (5 ml) were added in turn under ice-coolingtriethylamine (0.31 ml) and methanesulfonyl chloride (0.14 ml). Thissolution was stirred under ice-cooling for 15 minutes. After addingethyl acetate, the mixture was washed in turn with dilute hydrochloricacid, an aqueous solution of sodium hydrogencarbonate and saturatedbrine, dried over magnesium sulfate, and the solvent was distilled offunder reduced pressure. To a solution of the residue indimethylformamide (15 ml) was added cesium propionate (0.9 g), and themixture was stirred at 50° C. for 62 hours. Ethyl acetate was added, andthe mixture was washed in turn with water, dilute hydrochloric acid, anaqueous solution of sodium hydrogencarbonate and saturated brine, driedover magnesium sulfate, and the solvent was distilled off under reducedpressure. Potassium carbonate (14 mg) was added to a solution of theresidue in methanol (10 ml), the mixture was stirred at room temperaturefor 46 hours, and the solvent was then distilled off under reducedpressure. The residue was chromatographed over silica gel to give6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(0.28 g, yield=56%) from the fraction of ethyl acetate/hexane (2/1). TheHPLC-1 analysis of the optical isomer showed 95.5% purity (R/S=95.5/4.5,the purity of the material optical isomer used=96%).

EXAMPLE 22

To a solution of6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)carboxamide(0.5 g) in methylene chloride (8 ml) were added 4-dimethylaminopyridine(450 mg) and p-toluenesulfonyl chloride (560 mg) at room temperature,and the mixture was stirred for 24 hours. To the reaction solution wasadded chloroform, the solution was washed in turn with dilutehydrochloric acid, an aqueous solution of sodium hydrogencarbonate andsaturated brine, dried over magnesium sulfate, and the solvent wasdistilled off under reduced pressure. Dimethylformamide (13 ml) wasadded to the residue, and the mixture was stirred at 75° C. for 24hours, and then the solvent was distilled off under reduced pressure.Potassium carbonate (18 mg) was added to a solution of the residue inmethanol (10 ml), the mixture was stirred at room temperature for 21hours, and the solvent was distilled off under reduced pressure. Theresidue was chromatographed over silica gel to give6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(0.36 g, yield=72%) from the fraction of ethyl acetate/hexane (2/1). TheHPLC-1 analysis of the optical isomer showed 84% purity (R/S=84/16, thepurity of the material optical isomer used=96%).

EXAMPLE 23

6-(2-(S)-Hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide

To a solution of6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(1.0 g) in methylene chloride (16 ml) were added 4-dimethylaminopyridine(900 mg) and p-toluenesulfonyl chloride (1.12 g) at room temperature,and the solution was stirred for 24 hours. To the reaction solution wasadded chloroform, the mixture was washed in turn with dilutehydrochloric acid, an aqueous solution of sodium hydrogencarbonate andsaturated brine, dried over magnesium sulfate, and the solvent wasdistilled off under reduced pressure. To a solution of the residue indimethylformamide (10 ml) was added sodium acetate (250 mg), and themixture was stirred at 60° C. for 64 hours. Ethyl acetate was added andthe mixture was washed in turn with water, dilute hydrochloric acid, anaqueous solution of sodium hydrogencarbonate and saturated brine, driedover magnesium sulfate, and the solvent was distilled off under reducedpressure. To a solution of the residue in methanol (20 ml) was addedpotassium carbonate (42 mg), and the solution was stirred at roomtemperature for 24 hours. The solvent was distilled off under reducedpressure to give6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(yield=61%, the purity of the optical isomer=83.5% by HPLC-1 analysis(S/R=83.5/16.5, the purity of the material optical isomer used=96% )).Yield was calculated by HPLC-3 analysis.

EXAMPLE 24

To a solution of6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(0.5 g) in methylene chloride (8 ml) were added 4-dimethylaminopyridine(450 mg) and p-toluenesulfonyl chloride (560 mg) at room temperature,and the solution was stirred for 24 hours. To the reaction solution wasadded chloroform, the mixture was washed in turn with dilutehydrochloric acid, an aqueous solution of sodium hydrogencarbonate andsaturated brine, dried over magnesium sulfate, and the solvent wasdistilled off under reduced pressure. To a solution of the residue indimethylsulfoxide (5 ml) was added ammonium formate (280 mg), and themixture was stirred at 50° C. for 24 hours. To the solution was addedethyl acetate, and the mixture was washed in turn with dilutehydrochloric acid, an aqueous solution of sodium hydrogencarbonate andsaturated brine, dried over magnesium sulfate, and the solvent wasdistilled off under reduced pressure. To a solution of the residue inmethanol (20 ml) was added p-toluenesulfonic acid monohydrate (20 mg),the solution was stirred at 60° C. for one hour, and the solvent wasdistilled off under reduced pressure. To the solution was added ethylacetate, the mixture was washed in turn with water, dilute hydrochloricacid, an aqueous solution of sodium hydrogencarbonate and saturatedbrine, dried over magnesium sulfate. The solvent was distilled off underreduced pressure to give6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(yield=71%, the purity of the optical isomer=95% by HPLC-1 analysis(S/R=95/5, the purity of the material optical isomer used=96%)). Yieldwas calculated by HPLC-3 analysis.

EXAMPLE 25

To a solution of6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(7.0 g) in tetrahydrofuran (70 ml) were added in turn under ice-coolingtriethylamine (4.3 ml) and methanesulfonyl chloride (1.9 ml). Thissolution was stirred under ice-cooling for 15 minutes. After addingethyl acetate, the mixture was washed in turn with water, dilutehydrochloric acid, an aqueous solution of sodium hydrogencarbonate andsaturated brine, dried over magnesium sulfate, and the solvent wasdistilled off under reduced pressure. To a solution of the residue indimethylsulfoxide (21 ml) was added a solution of triethylamine (8.6ml)/formic acid (5.4 ml), and the mixture was stirred at 70° C. for 41hours. After adding ethyl acetate, the mixture was washed with water andsaturated brine in turn, dried over magnesium sulfate, and the solventwas distilled off under reduced pressure. p-Toluenesulfonic acidmonohydrate (40 mg) was added to a solution of the residue in methanol(50 ml), the mixture was stirred at 60° C. for one hour, and the solventwas distilled off under reduced pressure. To the solution was addedethyl acetate, the mixture was washed with an aqueous solution of sodiumhydrogencarbonate and saturated brine in turn, and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure to give6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(yield=69%, the purity of the optical isomer=92% by HPLC-1 analysis(S/R=92/8, the purity of the material optical isomer used=96%)). Yieldwas calculated by HPLC-3 analysis.

EXAMPLE 26

To a solution of6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(7.0 g) in methylene chloride (110 ml) were added4-dimethylaminopyridine (6.3 g) and p-toluenesulfonyl chloride (7.8 g)at room temperature, and the solution was stirred for 16 hours. To thereaction solution was added chloroform, the mixture was washed in turnwith dilute hydrochloric acid, an aqueous solution of sodiumhydrogencarbonate and saturated brine, dried over magnesium sulfate, andthe solvent was distilled off under reduced pressure. To a solution ofthe residue in dimethylsulfoxide (21 ml) was added a solution oftriethylamine(8.6 ml)/formic acid (5.4 ml), and the mixture was stirredat 70° C. for 9 hours. To the solution was added ethyl acetate, and themixture was washed with water and saturated brine in turn, dried overmagnesium sulfate, and the solvent was distilled off under reducedpressure. To a solution of the residue in methanol (50 ml) was addedp-toluenesulfonic acid monohydrate (340 mg), the solution was stirred at60° C. for one hour, and the solvent was distilled off under reducedpressure. To the solution was added ethyl acetate, the mixture waswashed with an aqueous solution of sodium hydrogencarbonate andsaturated brine in turn, and dried over magnesium sulfate. The solventwas distilled off under reduced pressure to give6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(yield=70%, the purity of the optical isomer=95% by HPLC-1 analysis(S/R=95/5, the purity of the material optical isomer used=96%)). Yieldwas calculated by HPLC-3 analysis.

EXAMPLE 27

To a solution of6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(7.0 g) in methylene chloride (110 ml) were added4-dimethylaminopyridine (6.3 g) and p-toluenesulfonyl chloride (7.8 g)at room temperature, and the solution was stirred for 16 hours. To thereaction solution was added chloroform, the mixture was washed in turnwith dilute hydrochloric acid, an aqueous solution of sodiumhydrogencarbonate and saturated brine, dried over magnesium sulfate, andthe solvent was distilled off under reduced pressure. To the residue wasadded a solution of triethylamine(8.6 ml)/formic acid (5.4 ml), and themixture was stirred at 60° C. for 28 hours. To a solution was addedethyl acetate, and the mixture was washed in turn with water, dilutehydrochloric acid, an aqueous solution of sodium hydrogencarbonate andsaturated brine, dried over magnesium sulfate, and the solvent wasdistilled off under reduced pressure. To a solution of the residue inmethanol (50 ml) was added p-toluenesulfonic acid monohydrate (350 mg),the solution was stirred at 60° C. for one hour, and the solvent wasdistilled off under reduced pressure. To the residue was added ethylacetate, the mixture was washed with an aqueous solution of sodiumhydrogencarbonate and saturated brine in turn, dried over magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was crystallized from xylene/hexane to give6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(5.6 g, yield=80%). HPLC-1 analysis of the optical isomer showed 92.5%purity (S/R=92.5/7.5, the purity of the material optical isomerused=96%)).

Reference Example 1

a) A suspension of6-formyl-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(208.15 g) and cyclohexylamine (84 ml) in benzene was heated underreflux using Dean-Stark apparatus for 1.5 hours. The reaction solutionwas distilled off under reduced pressure, nitroethane (144 ml) andacetic acid (750 ml) were added to the residue, and the mixture wasstirred at 110-120° C. for 2 hours. The reaction solution was distilledoff under reduced pressure, ethyl acetate was added to the residue, andthe mixture was washed with water three times. The solution was washedwith an aqueous solution of sodium hydrogencarbonate and saturated brinein turn, dried over magnesium sulfate, and filtered through Celite. Thesolvent was distilled off under reduced pressure to give a yellow solid(310 g).

¹H-NMR (CDCl₃) δ: 1.57 (d, 3H, 8H), 2.54 (s, 3H), 4.19 (dd, 1H, J=8 Hz,12 Hz), 4.57 (dd, 1H, J=3 Hz, 12 Hz), 4.77 (dd, 1H, J=3 Hz, 8 Hz), 5.19(quint, 1H, J=7 Hz), 6.75 (d, 1H, J=8 Hz), 7.00-7.05 (m, 3H), 7.17-7.32(m, 5H), 7.99 (s, 1H)

b) A suspension of the crude product (310 g) obtained in a) above inethanol (680 ml) was heated while stirring. After dissolving, ironpowder (186 g) and water (230 ml) were added. The solution was heated at70° C., and acetic acid (855 ml) was added dropwise over one hour. Aftercompletion of the dropwise addition, the solution was further heatedwhile stirring for one hour. The solution was cooled to roomtemperature, methanol (400 ml), 5% aqueous hydrochloric acid (375 ml)and Celite (18 g) were added thereto, and the mixture was stirred forone hour. After filtration through Celite, the solvent was distilled offunder reduced pressure. To the residue was added ethyl acetate, and thesolution was washed with 10% hydrochloric acid, water, a saturatedsolution of sodium hydrogencarbonate and saturated brine. After dryingover magnesium sulfate, the solvent was distilled off under reducedpressure. The residue was crystallized from ethanol/hexane to give6-(2-oxopropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(177g,yield=78%).

¹H-NMR (CDCl₃) δ: 1.55 (d, 1H, J=7 Hz), 2.24 (s, 3H), 3.55 (s, 2H), 4.13(dd, 1H, J=8 Hz, 12 Hz), 4.52 (dd, 1H, J=3 Hz, 12 Hz), 4.69 (dd, 1H, J=3Hz, 8 Hz), 5.18 (quint, 1H, J=8 Hz), 6.71 (dd, 1H, J=2 Hz, 8 Hz), 6.75(d, 1H, J=2 Hz), 6.78 (d, 1H, J=8 Hz), 6.92 (d, 1H, J=8 Hz), 7.18-7.32(m, 5H)

Reference Example 2

To a suspension of6-(2-oxopropyl)-2,3-dihydro1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(207 g) in methanol (1000 ml) was slowly added sodium borohydride (23 g)under ice-cooling. After 30 minutes, the solution reaction was allowedto stand at room temperature, and stirred for 2 hours. To the reactionsolution was added acetone, which was then distilled off under reducedpressure. To the residue was added chloroform, washed in turn with 1Naqueous solution of hydrochloric acid, a saturated solution of sodiumhydrogencarbonate and saturated brine. After drying over magnesiumsulfate, the solution was filtered through Celite, and the solvent wasdistilled off under reduced pressure to give6-(2-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide(207.45 g, quantitatively).

¹H-NMR (CDCl₃) δ: 1.25 (d, 3H, J=7 Hz), 1.57 (d, 1H, J=7 Hz), 2.59(dd,1H, J=8 Hz, 14 Hz), 2.69 (dd, 1H, J=6 Hz, 14 Hz), 3.95 (sext, 1H, J=7Hz), 4.14 (dd, 1H, J=8 Hz, 12 Hz), 4.52 (dd, 1H, J=3 Hz, 12 Hz), 4.68(dd, 1H, J=3 Hz, 8 Hz), 5.17 (quint, 1H, J=7 Hz), 6.72 (dd, 1H, J=2 Hz,8 Hz), 6.76 (d, 1H, J=2 Hz), 6.88 (d, 1H, qqw2J=8 Hz), 6.90 (d, 1H, J=8Hz), 7.18-7.32 (m, 5H).

What is claimed is:
 1. A compound of formula (1)

wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino.
 2. Acompound of formula (2)

wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino.
 3. Aprocess for preparing a compound of formula (1)

wherein R is as defined below and a compound of formula (2)

wherein R is as defined below, which comprises the steps of; reacting aracemate of formula (3)

wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino with anacylating agent in the presence of a hydrolase to give a compound offormula (4)

wherein R is as defined above and X is (C₁-C₄)acyl and a compound offormula (2)

wherein R is as defined above, followed by separation, and subjecting acompound of formula (4) to alcoholysis or hydrolysis.
 4. The processaccording to claim 3 wherein the hydrolase is lipase or esterase.
 5. Theprocess according to claim 3 wherein the acylating agent is lower fattyacids anhydride or lower carboxylic esters.
 6. A process for convertinga compound of formula (1) to a compound of formula (2), which comprisessulfonylating the compound of formula (1):

wherein R is R-1-phenylethylamino or (S)-1-phenylethylamino, into asulfonic acid ester thereof, and reacting the sulfonic acid esterthereof with dimethylformamide or a lower carboxylate, followed byhydrolysis or alcoholysis.
 7. A process converting a compound of formula(2) to a compound of formula (1), which comprises sulfonylating thecompound of formula (2):

wherein R is R-1-phenylethylamino or (S)-1-phenylethylamino, into asulfonic acid ester thereof, and reacting the sulfonic acid esterthereof with dimethylformamide or a lower carboxylate, followed byhydrolysis or alcoholysis.